The Molecular Basis for Restoring Function to Oncogenic p53 Mutants
- Author(s): Wallentine, Bradley Dale
- Advisor(s): Luecke, Hartmut
- et al.
The tumor suppressor p53 is the most commonly mutated gene in cancers, with approximately half of all tumors containing a p53 mutation. p53 normally functions to moderate cell growth, incite DNA repair, and induce apoptosis in response to cellular stresses. Mutation of p53 gene leads to the p53 protein losing its tumor suppressor activity within the cell. Despite being the most commonly mutated gene in cancer, there are currently no drugs in the clinic able to target p53 and restore its function as a tumor suppressor. This thesis work encompasses the use of structural and biophysical techniques to understand the molecular basis for restoring function to oncogenic p53 mutants. First, I helped solve the X-ray crystal structures of oncogenic and rescue mutations in p53 in order to better understand possible molecular mechanisms for restoring function to mutant p53 (Chapter 2). Next working with our collaborators, I helped establish that a small molecule that is able to restore activity to mutant p53 would likely act by thermodynamically stabilizing the p53 structure (Chapter 3). Last, I discovered a small molecule which greatly stabilizes mutant p53, causes cancer cells containing mutant p53 to undergo massive cell death, and is continuing to show great promise as a p53 reactivating pharmacophore (Chapter 4).